Sorafenib tosylate, 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide 4-methylbenzenesulfonate of the following formula
is marketed as Nexavar® by Bayer for treatment of advanced renal cell carcinoma (primary kidney cancer). It has also received “Fast Track” designation by the FDA for the treatment of advanced hepatocellular carcinoma (primary liver cancer).
Sorafenib and its salts, such as the tosylate salt and a process for preparation thereof are disclosed in WO 00/41698 A1.
WO 00/042012 A1 describes sorafenib base, pharmaceutically acceptable salts and their use.
WO 06/034796 A1 discloses processes for preparing sorafenib base and its tosylate salt.
WO 06/034797 reports crystalline forms of sorafenib tosylate, forms I, II, and III, methanol solvate, ethanol solvate and preparation thereof. Crystalline Sorafenib tosylate form III is characterized by a PXRD pattern having peaks selected from a list consisting of: 7.7, 8.5, 9.8, 10.6, 12.0, 12.3, 12.9, 13.4, 13.5, 15.4 and 16.0, 16.5, 16.9, 17.3, 17.8, 18.7, 18.8, 19.3, 19.9, 20.3, 20.8, 21.2, 21.6, 22.5, 23.0, 23.4, 24.2, 24.5, 24.8, 25.2, 25.9, 26.9, 27.5, 27.7, 28.2, 29.2, 29.4, 29.8, 30.3, 31.4, 32.2, 33.5, 34.0, 35.2, 36.1, 37.2, and 37.7±0.2 degrees 2theta. Crystalline Sorafenib tosylate methanol solvate is characterized by a PXRD pattern having peaks selected from a list consisting of: 8.0, 8.4, 9.3, 11.2, 12.2, 13.0, 13.4, 15.8, 16.3, 16.9, 17.7, 18.3, 18.7, 19.0, 19.4, 20.2, 20.5, 20.9, 21.4, 21.7, 22.3, 22.4, 23.8, 24.0, 24.4, 24.7, 24.9, 25.2, 25.7, 26.0, 26.1, 26.4, 26.9, 27.0, 27.5, 27.7, 28.1, 28.3, 28.8, 29.1, 29.7, 30.2, 30.4, 30.7, 30.8, 31.4, 31.6, 31.9, 32.3, 32.6, 32.9, 33.4, 33.8, 34.0, 34.2, 34.5, 34.9, 36.2, 36.6, 37.2, and 37.7±0.2 degrees 2theta. Crystalline Sorafenib tosylate ethanol solvate is characterized by a PXRD pattern having peaks selected from a list consisting of: 7.9, 8.4, 9.3, 9.5, 11.2, 12.0, 12.2, 12.8, 13.4, 15.9, 16.1, 16.8, 17.4, 17.7, 18.1, 18.3, 18.6, 18.8, 19.4, 20.0, 20.4, 21.0, 21.2, 21.5, 21.7, 22.3, 22.4, 22.8, 23.3, 23.6, 23.8, 24.3, 24.7, 25.3, 25.8, 25.9, 26.4, 26.9, 27.3, 27.6, 28.3, 28.8, 29.1, 29.5, 29.7, 30.2, 30.4, 30.9, 31.4, 32.0, 32.6, 32.9, 33.2, 33.7, 33.9, 34.5, 35.5, 36.0, 36.3, 36.6, 37.1, and 37.7±0.2 degrees 2theta.
The present invention discloses sorafenib hemi-tosylate, polymorphs of sorafenib hemi-tosylate and polymorphs of sorafenib tosylate, and processes for preparation thereof.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single compound, like sorafenib hemi-tosylate or sorafenib tosylate, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, x-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (“TGA”), and differential scanning calorimetry (“DSC”), which have been used to distinguish polymorphic forms.
The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.
One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubilities.
The discovery of new polymorphic forms and solvates of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. Therefore, there is a need for additional crystalline forms of sorafenib hemi-tosylate or sorafenib tosylate.